Abstract
The potential impact of structural variants includes not only the duplication or deletion of coding sequences, but also the perturbation of noncoding DNA regulatory elements and structural chromatin features, including topological domains (TADs). Structural variants disrupting TAD boundaries have been implicated both in cancer and developmental disease; this likely occurs via "enhancer hijacking," whereby removal of the TAD boundary exposes enhancers to new target transcription start sites (TSSs). With this functional role, we hypothesized that boundaries would display evidence for negative selection. Here we demonstrate that the chromatin landscape constrains structural variation both within healthy humans and across primate evolution. In contrast, in patients with developmental delay, variants occur remarkably uniformly across genomic features, suggesting a potentially broad role for enhancer hijacking in human disease.
Highlights
Structural variants [1,2,3] cannot only disrupt coding sequences through deletion, duplication, or inversion, but can perturb noncoding DNA regulatory elements, including enhancers and structural features of chromatin, with consequences in development and disease [4, 5]
To systematically test if topological domains (TADs) boundary disruptions are under purifying selection and compare their evolutionary constraint to that of other regulatory elements, we examined patterns of structural variation across evolutionary timescales from fixed differences between ape genomes to rare variants in human populations (Fig. 1)
Are deletions depleted in active chromatin states both in apes and the human population, and at CTCF sites and TAD boundaries
Summary
Structural variants [1,2,3] cannot only disrupt coding sequences through deletion, duplication, or inversion, but can perturb noncoding DNA regulatory elements, including enhancers and structural features of chromatin, with consequences in development and disease [4, 5]. As the ability of negative selection to purge a given variant from the population depends on how deleterious it is and how much time selection has had to act on it [29], we can infer relative levels of evolutionary constraint on TAD boundaries by comparing the frequency with which they are altered by structural variants to that of other genomic elements and chromatin states. We find that deletions are strongly depleted at active chromatin states and TAD boundaries This signature of negative selection is absent in patients with autism and developmental delay, where deletions occur remarkably uniformly across the genome, and in cancer, where deletions show a slight enrichment for disrupting otherwise important features. Together our analyses uncover a genomewide pattern of negative selection against deletions that could potentially alter chromatin structure and lead to enhancer hijacking
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